Head and Neck Pathology
Moderators: Dr. Christina MacMillan and Dr. Nina Gale
Case 8 -
Favor Atypical Parathyroid Adenoma with Cystic Degeneration and Prior Rupture
Dr. Jennifer Hunt
A 75-year old woman presented with a mass in the neck and swallowing symptoms. She was found to be
mildly hypercalcemic and a sestamibi scan identified an enlarged parathyroid gland located next to the
esophagus. Intra-operatively the surgeon reported that the gland was very difficult to remove because it
was extensively adherent to the esophagus and the vertebral fascia. An en bloc resection was performed.
Case 8 - Slide 1
Diagnosis before additional history: Favor parathyroid carcinoma
Additional history obtained after surgery, frozen section, and final diagnosis:
The patient had trauma to the neck 1 year prior to surgery due to a motor vehicle accident. Scans
revealed a large cystic mass near the esophagus that had ruptured. A week later, she experienced severe
bruising of the neck and chest that seemed to be unrelated to the actual physical insult.
Diagnosis after additional history: Favor atypical parathyroid adenoma with cystic degeneration and prior rupture.
Case Eight Discussion
Hyperparathyroidism is relatively common with some estimates of incidence in European countries of 3-4
per 1,000 .
Comparable numbers would be expected in the United States
hyperparathyroidism are primary, secondary, or tertiary (TABLE 2)
Patients with hyperparathyroidism can be asymptomatic with hypercalcemia identified on routine health
screens, or they may be very symptomatic with an increased risk of hypertension, nephrolithiasis,
osteoporotic fractures or cardiovascular complications
TABLE 2: Causes of hyperparathyroidism
|Type ||Description ||Causes|
|Primary Hyperparathyroidism ||Parathyroid related disease ||Parathyroid adenoma |
Parathyroid hyperplasia (genetic)
|Secondary Hyperparathyroidism ||Secretion of parathyroid hormone in response to low calcium from another disease ||Rickets (Osteomalacia) due to vitamin D or calcium deficiency) |
Chronic renal failure
|Tertiary Hyperparathyroidism ||One parathyroid gland becoming autonomous after persistent secondary hyperparathyroidism |
The treatment of most types of hyperparathyroidism is usually surgical
are several known risks of surgery, including damage to the recurrent laryngeal nerve and permanent
hypoparathyroidism . Historically, abnormal or enlarged glands are surgically excised, the weight is
obtained, and frozen sections are performed to confirm the presence of parathyroid tissue
cases of adenoma or carcinoma, shave biopsy of at least one normal sized gland has been routinely
practiced to rule out the possibility of unrecognized heterogeneous hyperplasia, which can result in
operative failure and/or recurrent hyperparathyroidism.
Parathyroid cysts are considered to be rare, with the exception of cystic degeneration of
a parathyroid neoplasm. In one study of 25 years worth of parathyroid surgery (and over 22,000 thyroid
and parathyroid specimens), 37 patients were identified to have parathyroid cysts . Parathyroid
cysts are usually non-functional, with only rare cases of hyperparathyroidism being reported with
The cysts presented primarily as mass lesions, either as known parathyroid
cysts (from fluid sampling with parathyroid hormone assays) or as "thyroid nodules"
are generally located in the neck, but also can extend into the mediastinum . Other parathyroid
lesions can also be found in the mediastinum .
Histologically, parathyroid cysts are usually lined by a non-descript epithelium that is
low and cuboidal . The epithelium may be vacuolated as well. In the wall of the cysts, there is
usually some residual parathyroid tissue, forming typical nests. Parathyroid hormone
immunohistochemistry stains and CK19 will be positive, as will chromogranin and synaptophysin.
Interesting, parathyroid cysts are often associated with other types of tissue as well
This can include salivary gland heterotopia, thymic remnants, or other stromal elements
(smooth muscle, adipose and fibrous tissues). This raises the possibility that parathyroid cysts may
represent hamartomas or benign embryologic rests .
The differential diagnosis for these lesions will include other neck cysts, particularly
before histological sampling. The primary neck cysts that may be considered would be branchial cleft
cyst, thyroglossal duct cyst, and thymic cysts . These benign lesions range from common (branchial
and thyroglossal duct cysts) to rare (thymic cysts). The histology and characteristic locations should
help in making this diagnosis. But, in the case of overlapping features, a parathyroid hormone stain
will certainly determine the true etiology of a parathyroid cyst.
One interesting association has been reported between cysts in parathyroid and the genetic
disease hyperparathyroidismójaw tumor syndrome (HPT-JT). This syndrome is linked to a region of a
presumed tumor suppressor gene on 1q32. When histologically sampled, many of the parathyroid lesions in
these patients will be cystic and sometimes this syndrome may be referred to as cystic parathyroid
adenomatosis . Patients with this syndrome have an increased risk of developing carcinoma, which is
seen in10-15% of patients with HPT-JT.
Adenoma and Carcinoma
The majority of patients with primary hyperparathyroidism will have a single glandular abnormality.
These patients usually present with incidental hypercalcemia, found at routine health screenings. A
sestamibi scan can help the surgeon to pre-operatively locate the abnormal gland, but these may be
nonspecific and thus exploration during surgery may still be needed. In the setting of
hyperparathyroidism, a single enlarged parathyroid gland will be surgically excised, in a conservative
operation in order to not harm the recurrent laryngeal nerve or other critical structures in the neck.
The other glands may be explored, particularly if there is a concern of the possibility of either double
adenoma or asynchronous hyperplasia.
The first step in assessing a parathyroid gland it the determination if the gland is enlarged. Most
people use the weight as the most accurate measurement of the size of a parathyroid gland . The
normal weight of the parathyroid gland should be less than 60 mg. But, in an autopsy study, normal
glands had a median weight of 26 mg (range 8 to 75 mg); lower weights were seen in patients with chronic
diseases . Some investigators have also used the size of the gland, though standard measurements
have not been nearly so well established .
Parathyroid adenomas are almost always enlarged by weights (i.e. > 60 mg). The mean weight of a
parathyroid adenoma is around 500 mg (range 55 to >3000 mg) . The parathyroid adenoma will have
typical histologic findings. The cellular composition may include show predominantly a single cell type,
or can show mixed features . The most common type of cell to predominate is the chief cell, though
oncocytes can also be dominant
Occasionally parathyroid adenomas designated as "water
clear cell adenomas" have been described in the literature. The cells in these lesions are composed of
polygonal cells with very clear cytoplasm and distinct cytoplasmic borders . Parathyroid hormone
levels may be very low in these lesions . Other morphologic features of parathyroid adenoma may
include a rim of normal somewhat suppressed parathyroid tissue around the outside of the gland. This can
be used as a diagnostic clue for the etiology of the pathologic process. Mitoses are usually rare to
absent in parathyroid adenomas
The differential diagnosis between benign adenoma and carcinoma cannot be reliably made just based on
the histologic assessment alone (TABLE 3). The surgeon's intraoperative
opinion about adherence to surrounding structures is an important criterion in distinguishing benign from
malignant parathyroid neoplasms. The surgeon who encounters a parathyroid carcinoma will describe the
gland as "sticky," "fibrotic," "hypervascular," or "adherent to local structures"
descriptions should immediately alert the pathologist to the possibility of parathyroid carcinoma. The
histologic features of malignancy may not all be seen in a given case
There are some
histopathologic features which are associated with malignancy, though they are certainly not
pathognomonic for carcinoma. Worrisome features include the presence of increased or atypical mitoses,
broad bands of fibrosis, trabecular growth pattern, invasion of adjacent tissue, and perineural or
angiolymphatic invasion . These features usually correlate with malignancy, though these histologic
features are not always present in every case of parathyroid carcinoma
carcinomas tend to be locally invasive and invasion is most commonly seen into the thyroid gland, strap
muscles, recurrent laryngeal nerve, esophagus or trachea
TABLE 3: Clinical and histologic features of parathyroid carcinoma
|Clinical Features ||Histologic Features|
|High calcium level (>14 mg/dl) ||Trabecular growth|
|Parathyroid hormone level > 5 x normal ||Broad intersecting fibrous bands|
|Palpable mass lesion ||Increased mitoses|
|Bone symptoms ||Stromal invasion|
|Operative findings of invasive growth (sticky, fibrotic, vascular gland) ||Angiolymphatic or perineural invasion|
In the final analysis, it may be difficult to make a diagnosis of parathyroid carcinoma. In some
cases, the clinical impression of parathyroid cancer does not correlate with the pathologic or
microscopic impression. Therefore these cases are often labeled as "atypical adenoma", and because of
diagnostic ambiguity, the true diagnosis may only be resolved with long term follow-up
The differential diagnosis for an atypical parathyroid lesion with histologic features worrisome for
malignancy can include parathyroid adenomas or cyst that undergo degenerative changes from rupture or
trauma; sometimes these features are also seen in the re-operative setting or in persons with neck
surgery for other reasons. The presence of hemosiderin and degenerative changes can be helpful in making
this diagnosis . Parathyroid cyst rupture can be accompanied by an unusual clinical finding of
hematoma and subsequent severe skin bruising . Finally, in patients who have primary parathyroid
surgery with spillage during the operation, parathyromatosis can develop . In this condition,
remnant parathyroid nests and clusters can be located throughout the neck tissues .
For many years, parathyroid carcinoma was thought of as a lethal disease with a terrible prognosis.
This prognosis was probably partially related to non-uniform treatment and incomplete excision in some
patients. The treatment of choice for parathyroid carcinoma is an en bloc resection with clear margins
. Most series of patients with parathyroid carcinoma with optimal treatment have shown recurrence
rates of <10% and 5-year survivals of nearly 90% (~65-70% survival at 10-years)
of the reason behind the misconceptions about prognosis is the fact that some cases of parathyroid
carcinoma have minimal invasion and very few other features of malignancy. These probably represent the
lowest grade form of the disease, but no grading system is in place. At the other end of the spectrum
will be rare patients who have aggressive malignancies with widespread invasion. One recent report
suggested classifying minimally invasive tumors as low grade and widely invasive tumors as high grade
There have been some studies of the molecular mutational findings in parathyroid neoplasia. One
feature that is consistently noted is that parathyroid adenomas and carcinomas have a high rate of loss
of the short arm of chromosome one (1p)
This is not a feature that is generally seen in
parathyroid hyperplasia. Other genes have also been implicated in parathyroid adenomas and carcinomas,
including Retinoblastoma (RB, 13q14.3), the MEN
gene (11q13), and the BRCA2 gene (13q12.3)
Studies of a very
interesting syndrome (hyperparathyroidismójaw tumor syndrome) have also provided insight into the
pathogenesis of parathyroid neoplasia. A tumors suppressor gene has been identified, mapping to 1q25-31
and designated as HPRT2 that harbors germline mutations in hereditary cases of this syndrome. But, loss
of heterozygosity and somatic point mutations have also been detected in sporadic parathyroid carcinomas
The burden of loss of heterozygosity type of mutations across s a series of tumor suppressor
genes has also been shown to correlate with the presence of malignancy .
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